Heterocyclic substituted piperazinone derivatives

ABSTRACT

The present invention relates to substituted piperazinone derivatives of formula (1) or stereoisomers, or pharmaceutically acceptable salts thereof and their use as tachykinin receptor antagonists. Such antagonists are useful in the treatment of tachykinin-mediated diseases and conditions disclosed herein including: asthma, cough, and bronchitis. The present invention also relates to intermediates useful in the preparation of compounds of formula (1).

This application is a divisional of application Ser. No. 08/878,695,filed Jun. 19, 1997, which is a continuation of Ser. No. 08/404,788,filed Mar. 15, 1995, now abandoned, which is herein incorporated byreference.

The present invention relates to substituted piperazinone derivatives(herein referred to as compounds or compounds of formula (1)) orstereoisomers, or pharmaceutically acceptable salts thereof and theiruse as tachykinin receptor antagonists. Such antagonists are useful inthe treatment of tachykinin-mediated diseases and conditions disclosedherein including: asthma, cough, and bronchitis. The present inventionalso relates to compounds of formula (2) useful as intermediates in thepreparation of compounds of formula (1).

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula (1): ##STR1##wherein G₁ is --CH₂ -- or --C(O)--;

Ar₁ is a radical chosen from the group: ##STR2## wherein Z₁ is from 1 to3 substituents each independently chosen from the group consisting ofhydrogen, halogen, benzyloxy, hydroxy, CF₃, C₁ -C₄ alkyl, and C₁ -C₄alkoxy;

R₁ is hydrogen, a radical of the formula, ##STR3## or --(CH₂)_(q) Ar₂,or --CH₂ C(O)Ar₂ wherein

q is an integer from 1 to 4 and Ar₂ is a radical of the formula ##STR4##wherein Z₂ is from 1 to 3 substituents each independently chosen fromthe group consisting of hydrogen, halogen, benzyloxy, hydroxy, CF₃, C₁-C₄ alkyl, and C₁ -C₄ alkoxy;

R₂ is hydrogen, C₁ -C₄ alkyl, or --CHO;

R₃ is hydrogen or a radical chosen from the group ##STR5## wherein Z₃ isfrom 1 to 3 substituents each independently chose n from the groupconsisting of hydrogen, halogen, benzyloxy, hydroxy, CF₃, C₁ -C₄ alkyl,and C₁ -C₄ alkoxy;

or stereoisomers, or pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention relates to compounds,which are useful intermediates in the preparation of compounds of theformula (1), the compounds of formula (2): ##STR6## wherein Ar₁ is aradical chosen from the group: ##STR7## wherein Z₁ is from 1 to 3substituents each independently chosen from the group consisting ofhydrogen, halogen, benzyloxy, hydroxy, CF₃, C₁ -C₄ alkyl, and C₁ -C₄alkoxy;

R₂ is hydrogen, C₁ -C₄ alkyl, or --CHO;

R₃ is hydrogen or a radical chosen from the group ##STR8## wherein Z₃ isfrom 1 to 3 substituents each independently chosen from the groupconsisting of hydrogen, halogen, benzyloxy, hydroxy, CF₃, C₁ -C₄ alkyl,and C₁ -C₄ alkoxy;

R₅ is hydrogen, benzyl, or C₁ -C₄ alkyl;

R₆ is hydrogen or --C(O)OR₇ wherein R₇ is benzyl or C₁ -C₄ alkyl;

or stereoisomers, or pharmaceutically acceptable salt thereof.

As is appreciated by one of ordinary skill in the art the compounds ofthe formula (1) and formula (2) exist as stereoisomers. TheCahn-Ingold-Prelog designation of (R)- and (S)- for the stereochemistryof compounds represented by formula (1) and formula (2) depends on thenature of the substituents present. Any reference in this application toone of the compounds of the formula (1) and formula (2) is meant toencompass either specific stereoisomers or a mixture of stereoisomers.The specific stereoisomers can be prepared by stereospecific synthesisor can be separated and recovered by techniques known in the art, suchas chromatography on chiral stationary phases, amide formation with achiral acid followed by separation of the resultant diastereomericamides and hydrolysis to the desired stereoisomer, or fractionalrecrystallization of addition salts formed by reagents used for thatpurpose, as described in "Enantiomers, Racemates, and Resolutions", J.Jacques, A. Collet, and S. H. Wilen, Wiley (1981).

As used in this application:

a) the term "halogen" refers to a fluorine atom, chlorine atom, bromineatom, or iodine atom;

b) the term "C₁ -C₄ alkyl" refer to a branched or straight chained alkylradical containing from 1 to 4 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc;

c) the term "C₁ -C₄ alkoxy" refer to a straight or branched alkoxy groupcontaining from 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, t-butoxy, etc;

(d) the designation --C(O)-- or C(O) refers to a carbonyl group of theformula: ##STR9## e) the designation "" refers to a bond for which thestereochemistry is not designated.

f) as used in the preparations and examples; the term "g" refers tograms; the term "mg" refers to milligrams; the term "kg" refers tokilograms; the term "mmol" refers to millimoles; the term "mL" refers tomilliliters; the term "°C" refers to degrees Celsius the term "R_(f) "refers to retention factor; the term "mp" refers to melting point; theterm "dec" refers to decomposition; the term "THF" refers totetrahydrofuran; the term "DMF" refers to dimethylformamide; the term "α!² _(D) ⁰ " refer to specific rotation of the D line of sodium at 20°C. obtained in a 1 decimeter cell; the term "c" refers to concentrationin g/mL; the term "DMSO" refers to dimethyl sulfoxide; the term "M"refers to molar; the term "HPLC" refers to high performance liquidchromatography; the term "HRMS" refers to high resolution mass spectrum;

g) by the designation ##STR10## it is understood that the radical isattached at the 1-position and the substituent or substituentsrepresented by Z can be attached in any of the 2, 3, 4, 5, or 6positions;

h) by the designation ##STR11## it is understood that the radical can beattached at the either the 1-position or the 2-position, it is furtherunderstood that when the radical is attached at the 1-position thesubstituent or substituents represented by Z can be attached in any ofthe 2, 3, 4, 5, 6, 7, or 8 positions and that when the radical isattached at the 2-position the substituent or substituents representedby Z can be attached in any of the 1, 3, 4, 5, 6, 7, or 8 positions;

i) the term "pharmaceutically acceptable salts thereof" refers to eitheran acid addition salt or a basic addition salt.

The expression "pharmaceutically acceptable acid addition salts" isintended to apply to any non-toxic organic or inorganic acid additionsalt of the base compounds represented by formula (1) or formula (2).Illustrative inorganic acids which form suitable salts includehydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metalsalts such as sodium monohydrogen orthophosphate, and potassium hydrogensulfate. Illustrative organic acids which form suitable salts includethe mono-, di-, and tricarboxylic acids. Illustrative of such acids arefor example, acetic, glycolic, lactic, pyruvic, malonic, succinic,glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic,hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic,salicyclic, 2-phenoxy-benzoic, p-toluenesulfonic acid, and sulfonicacids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid.Such salts can exist in either a hydrated or substantially anhydrousform. In general, the acid addition salts of these compounds are solublein water and various hydrophilic organic solvents, and which incomparison to their free base forms, generally demonstrate highermelting points.

The expression "pharmaceutically acceptable basic addition salts" isintended to apply to any non-toxic organic or inorganic basic additionsalts of the compounds represented by formula (1) or formuala (2).Illustrative bases which form suitable salts include alkali metal oralkaline-earth metal hydroxides such as sodium, potassium, calcium,magnesium, or barium hydroxides; ammonia, and aliphatic, alicyclic, oraromatic organic amines such as methylamine, dimethylamine,trimethylamine, and picoline. Either the mono- or di-basic salts can beformed with those compounds.

As with any group of structurally related compounds which possesses aparticular generic utility, certain groups and configurations arepreferred for the compounds of formula (1) and formula (2) in theirend-use application.

Preferred embodiments of formula (1) are given below:

1) Compounds in which R₁ is hydrogen or --CH₂ C(O)Ar₂ are preferred;

2) Compounds in which G₁ --C(O)-- are preferred;

3) Compounds in which R₂ is hydrogen are preferred;

4) Compounds in which R₃ is hydrogen are preferred;

5) Compounds in which Ar₁ is the radical ##STR12## are preferred.

It is understood that further preferred embodiments of formula (1) canbe selected by requiring one or more of the preferred embodiments 1through 5 of formula (1) or by reference to examples given herein.

Preferred embodiments of formula (2) are given below:

1) Compounds in which R₅ is methyl are preferred;

2) Compounds in which R₆ is --C(O)OR₇ wherein R₇ is t-butyl arepreferred;

3) Compounds in which R₂ is hydrogen are preferred;

4) Compounds in which R₃ is hydrogen are preferred;

5) Compounds in which Ar₁ is the radical ##STR13## are preferred.

It is understood that further preferred embodiments of formula (2) canbe selected by requiring one or more of the preferred embodiments 1through 5 of formula (2) or by reference to examples given herein.

Illustrative of compounds encompassed by the present invention includethe following. This list is meant to be representative only and is notintended to limit the scope of the invention in any way:

(R)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1-(2,2-bis-phenyl-ethyl)-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1-(2,2-bis-phenyl-ethyl)-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(hydroxy)phenyl!ethyl!!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(hydroxy)phenyl!ethyl!-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-4-2-(1H-indol-3-yl)-2-oxo-ethyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-4-2-(1H-indol-3-yl)-2-oxo-ethyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-4-2-(1H-indol-3-yl)-2-oxo-ethyl!-1-(2,2-bis-phenyl-ethyl)-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-4-2-(1H-indol-3-yl)-2-oxo-ethyl!-1-(2,2-bis-phenyl-ethyl)-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-4- 2-(1H-indol-3-yl)-2-oxo-ethyl!-1- 2-4-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-4- 2-(1H-indol-3-yl)-2-oxo-ethyl!-1- 2-4-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-4- 2-(1H-indol-3-yl)-2-oxo-ethyl!-1- 2-4-(hydroxy)phenyl!ethyl!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-4- 2-(1H-indol-3-yl)-2-oxo-ethyl!-1- 2-4-(hydroxy)phenyl!ethyl!-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-4-(S)-pyroglutamoyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-4-(S)-pyroglutamoyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-4-(R)-pyroglutamoyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-4-(R)-pyroglutamoyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-4-2-phenyl-2-oxo-ethyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-4-2-phenyl-2-oxo-ethyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-4-(phenyl)methyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-4-(phenyl)methyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1-(2-naphth-2-yl-ethyl)-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1-(2-naphth-2-yl-ethyl)-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1-(2-naphth-1-yl-ethyl)-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1-(2-naphth-1-yl-ethyl)-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(chloro)phenyl!ethyl!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(chloro)phenyl!ethyl!-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(fluoro)phenyl!ethyl!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(fluoro)phenyl!ethyl!-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(methyl)phenyl!ethyl!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(methyl)phenyl!ethyl!-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(methoxy)phenyl!ethyl!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(methoxy)phenyl!ethyl!-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(trifluoromethyl)phenyl!ethyl!-2-oxo-piperazine;(S)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(trifluoromethyl)phenyl!ethyl!-2-oxo-piperazine;

(R)-3(R)-3-(1H-Indol-3-ylmethyl)-1- 2-2-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1- 2-2-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-2-(hydroxy)phenyl!ethyl!!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1- 2-2-(hydroxy)phenyl!ethyl!-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-3-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1- 2-3-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-3-(hydroxy)phenyl!ethyl!!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1- 2-3-(hydroxy)phenyl!ethyl!-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-2-(chloro)phenyl!ethyl!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1- 2-2-(chloro)phenyl!ethyl!-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-2-(fluoro)phenyl!ethyl!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1- 2-2-(fluoro)phenyl!ethyl!-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-2-(methyl)phenyl!ethyl!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1- 2-2-(methyl)phenyl!ethyl!-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-2-(methoxy)phenyl!ethyl!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1- 2-2-(methoxy)phenyl!ethyl!-2-oxo-piperazine;

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-2-(trifluoromethyl)phenyl!ethyl!-2-oxo-piperazine;

(S)-3-(1H-Indol-3-ylmethyl)-1- 2-2-(trifluoromethyl)phenyl!ethyl!-2-oxo-piperazine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2-phenyl-ethyl)-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2-phenyl-ethyl)-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-2- (4-benzyloxy)phenyl-ethyl!!-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-2- (4-benzyloxy)phenyl-ethyl!!-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2,2-bis-phenyl-ethyl)!-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2,2-bis-phenyl-ethyl)!-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2-naphth-2-yl-ethyl)-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2-naphth-2-yl-ethyl)-ethylamine;p0 2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2-naphth-1-yl-ethyl)-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2-naphth-1-yl-ethyl)-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 4-(chloro)phenyl-ethyl!!-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 4-(chloro)phenyl-ethyl!!-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 4-(fluoro)phenyl-ethyl!!-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 4-(fluoro)phenyl-ethyl!!-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 4-(methyl)phenyl-ethyl!!-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 4-(methyl)phenyl-ethyl!!-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 4-(methyloxy)phenyl-ethyl!!-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 4-(methyloxy)phenyl-ethyl!!-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 4-(triflurormethyl)phenyl-ethyl!!-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-((2-4-(triflurormethyl)phenyl-ethyl!!-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 2-(benzyloxy)phenyl-ethyl!!-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 2-(benzyloxy)phenyl-ethyl!!-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 3-(benzyloxy)phenyl-ethyl!!-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 3-(benzyloxy)phenyl-ethyl!!-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 2-(chloro)phenyl-ethyl!!-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 2-(chloro)phenyl-ethyl!!-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 2-(fluoro)phenyl-ethyl!!-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 2-(fluoro)phenyl-ethyl!!-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 2-(methyl)phenyl-ethyl!!-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 2-(methyl)phenyl-ethyl!!-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 2-(methyloxy)phenyl-ethyl!!-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 2-(methyloxy)phenyl-ethyl!!-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 2-(triflurormethyl)phenyl-ethyl!!-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2- 2-(triflurormethyl)phenyl-ethyl!!-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2-phenyl-ethyl)-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2-phenyl-ethyl)-ethylamine;

2- (R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- 2-(4-benzyloxy)phenyl-ethyl!!-ethylamine;

2- (S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- 2-(4-benzyloxy)phenyl-ethyl!!-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2,2-bis-phenyl-ethyl)!-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2,2-bis-phenyl-ethyl)!-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2-naphth-2-yl-ethyl)-ethylamine;

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2-naphth-2-yl-ethyl)-ethylamine;

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2-naphth-1-yl-ethyl)-ethylamine;2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2-naphth-1-yl-ethyl)-ethylamine;

2- (R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-4-(chloro)phenyl-ethyl!!-ethylamine;

2- (S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-4-(chloro)phenyl-ethyl!!-ethylamine;

2- (S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-4-(fluoro)phenyl-ethyl!!-ethylamine;

2- (R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-4-(fluoro)phenyl-ethyl!!-ethylamine;

2- (S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-4-(methyl)phenyl-ethyl!!-ethylamine;

2- (R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-4-(methyl)phenyl-ethyl!!-ethylamine;

2- (S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-4-(methyloxy)phenyl-ethyl!!-ethylamine;

2- (R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-4-(methyloxy)phenyl-ethyl!!-ethylamine;

2- (S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-4-(triflurormethyl)phenyl-ethyl!!-ethylamine;

2- (R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-4-(triflurormethyl)phenyl-ethyl!!-ethylamine;

2- (S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-2-(benzyloxy)phenyl-ethyl!!-ethylamine;

2- (R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-2-(benzyloxy)phenyl-ethyl!!-ethylamine;

2- (S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-3-(benzyloxy)phenyl-ethyl!!-ethylamine;

2- (R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-3-(benzyloxy)phenyl-ethyl!!-ethylamine;

2- (R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-2-(chloro)phenyl-ethyl!!-ethylamine;

2- (S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-2-(chloro)phenyl-ethyl!!-ethylamine;

2- (S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-2-(fluoro)phenyl-ethyl!!-ethylamine;

2- (R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-2-(fluoro)phenyl-ethyl!!-ethylamine;

2- (S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-2-(methyl)phenyl-ethyl!!-ethylamine;

2- (R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-2-(methyl)phenyl-ethyl!!-ethylamine;

2- (S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-2-(methyloxy)phenyl-ethyl!!-ethylamine;

2- (R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-2-(methyloxy)phenyl-ethyl!!-ethylamine;

2- (S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-2-(triflurormethyl)phenyl-ethyl!!-ethylamine;

2- (R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- (2-2-(triflurormethyl)phenyl-ethyl!!-ethylamine.

A general synthetic procedure is set forth in Scheme A for preparingthese compounds of formula (1). The reagents and starting materials arereadily available to one of ordinary skill in the art. In Scheme A, allsubstituents, unless otherwise indicated, are as previously defined.##STR14##

In Scheme A, step a, an appropriate amine of structure (3) or a saltthereof and an appropriate aldehyde of structure (4) are contacted within a reductive amination to give a compound of formula (2) in which R₆is --C(O)OR₇.

An appropriate amine of structure (3) is one in which R₂ and R₅ are asdefined for formula (2) and the stereochemistry is as desired in thefinal product of formula (1). For the preparation of compounds offormula (1), an amine of structure (3) in which R₅ is methyl ispreferred. An appropriate aldehyde of structure (4) is one in which theAr₁ and R₃ are as desired in the product of formula (1) or give riseafter deprotection to a group as desired in the final product of formula(1) and R₆ is --C(O)OR₇ as defined for formula (2). For the preparationof compounds of formula (1), an aldehyde of structure (4) in which R₇ ist-butyl is preferred.

For example, an appropriate aldehyde of structure (4) is contacted withan appropriate amine of structure (3) or a salt thereof in a reductiveamination. The reaction is carried out using a molar excess of asuitable reducing agent such as sodium borohydride or sodiumcyanoborohydride with sodium cyanoborohydride being preferred. Thereaction is carried out in a suitable solvent, such as methanol,dimethylformamide, dichloromethane, methanol/dimethylformamide mixtures,and methanol/dichloromethane mixtures. The reaction is carried out attemperatures of from 0° C. to 50° C. The reaction generally requires 24to 72 hours. The product can be isolated and purified by techniques wellknown in the art, such as extraction, evaporation, chromatography, andrecrystallization.

In Scheme A, step b, a compound of formula (2) in which R₆ is --C(O)OR₇is deprotected to give a compound of formula (2) or a salt thereof inwhich R₆ is hydrogen.

For example, a compound of formula (2) in which R₆ is --C(O)OR₇ in whichR₇ is t-butyl is reacted with a protic acid, such as hydrochloric acidor trifluoroacetic acid. The reaction is carried out in a solvent, suchas water, ethyl acetate, dioxane, methanol, or ethanol. The reactiongenerally requires from 1 to 48 hours and is carried out at temperaturesof from -20° C. to 50° C. The product can be isolated and purified bytechniques well known in the art, such as extraction, evaporation,chromatography, and recrystallization. The removal of protecting groupsother that --C(O)OR₇ in which R₇ is t-butyl is well known andappreciated in the art.

In Scheme A, optional step c, a compound of formula (2) in which R₆ ishydrogen or a salt thereof undergoes a cyclization reaction to give acompound of the formula (1) in which G₁ is --C(O)-- and R₁ is hydrogen.

For example, a compound of formula (2) in which R₆ is hydrogen or a saltthereof is cyclized. The reaction is carried out at the refluxtemperature of a suitable solvent, such as toluene or xylene. When asalt of a compound of formula (2) in which R₆ is hydrogen is used thereaction is carried out in the presence of about an equimolar amount ofa suitable base, such as triethylamine, diisopropylethylyamine, orpyridine. The reaction generally requires from 12 to 72 hours. Theproduct can be isolated and purified by techniques well known in theart, such as extraction, evaporation, chromatography, andrecrystallization.

Alternately, the compounds of formula (1) can be prepared form compoundsof formula (2) by Scheme A, optional steps d and e, as taught below.

In Scheme A, optional step d, a compound of formula (2) in which R₅ isC₁ -C₄ alkyl is hydrolyzed to give a compound of formula (2) in which R₅is hydrogen. The hydrolysis of esters, such as those described inProtecting Groups in Organic Synthesis by T. Greene is well known andappreciated in the art.

For example, a compound of formula (2) in which R₅ is C₁ -C₄ alkyl isreacted with a suitable hydrolyzing agent, such as sodium hydroxide,potassium hydroxide, lithium hydroxide, or sodium carbonate. Thereaction is carried out in a suitable solvent, such as water orwater/methanol mixtures, water/ethanol mixtures, water/tetrahydrofuranmixtures. The reactions are carried out at temperatures of from 0° C. tothe refluxing temperature of the solvent and generally require from 30minutes to 48 hours. The product can be isolated and purified bytechniques well known in the art, such as acidification, extraction,evaporation, chromatography, and recrystallization.

In Scheme A, optional step e, a compound of formula (2) in which R₆ andR₅ are hydrogen or a salt thereof undergoes a cyclization reaction togive a compound of the formula (1) in which G1 is --C(O)-- and R₁ ishydrogen. This cyclization reaction may proceed through an activatedintermediate, such as a mixed anhydride or a (O)--hydroxybenzotriazole,which may be prepared but is not necessarily isolated before thecyclization.

For example, a compound of formula (2) in which R₆ and R₅ are hydrogenor a salt thereof is contacted with about an equimolar amount of1-hydroxybenzotriazole hydrate in the presence of a slight molar excessof a suitable coupling agent, such as dicyclohexylcarbodiimide or1-(3-dimethyaminopropyl)-3-ethylcarbodiimide. The reaction is carriedout in the presence of a suitable base, such as diisopropylethyl amine.The reaction is carried out in a suitable solvent, such asdichloromethane, chloroform, ethyl acetate, and dimethylformamide; andat temperatures of from -50° C. to the refluxing temperature of thesolvent. The reaction generally requires from 1 hour to 48 hours. Theproduct can be isolated and purified by techniques well known in theart, such as extraction, evaporation, chromatography, andrecrystallization.

As is appreciated to one skilled in the art, in Scheme A the order inwhich optional step d and step b are carried out will depend on thecompound of formula (2) which is used and the compound of formula (1)which is desired. For some of the compounds of formula (2), it may beadvantageous to carry out an ester hydrolysis, optional step d, beforethe removal of the group R₆, which is --C(O)OR₇, in step b.

In Scheme A, optional step f, a compound of formula (1) may bedeprotected or modified to give a compound of formula (1).

A deprotection reaction encompasses the hydrolysis of esters, theremoval of a hydroxy protecting group, the removal of an indoleprotecting group, or the removal of an amino protecting group. Theselection, use, and removal of protecting groups utilizing suitableprotecting groups such as those described in Protecting Groups inOrganic Synthesis by T. Greene is well known and appreciated in the art.

A modification reaction encompasses the formation of amides, thealkylation of an amine, an addition reaction to an indole nitrogen, andthe formation of an amidate. A compound of formula (1) in which R₁ ishydrogen is alkylated with an appropriate alkylating agent to give acompound of formula (1) in which R₁ is C₁ -C₄ alkyl, --(CH₂)_(q) Ar₂, or--CH₂ C(O)Ar₂. An appropriate alkylating agent is one which transfers aC₁ -C₄ alkyl, --(CH₂)_(q) Ar₂, or --CH₂ C(O)Ar₂, such as iodomethane,bromomethane, iodoethane, bromoethane, bromopropane, bromobutane,benzylbromide, benzylchloride, phenethylbromide, phenethylchloride,3-chloro-1-phenyl-propane, 4-chloro-1-phenyl-butane,α-chloroacetophenone, α-bromoacetophenone, 3- (chloro)acetyl!-indole,etc.

For example, a deprotection may involve a compound of formula (1) inwhich Ar₁ is benzyloxy substituted is deprotected to give a compound offormula (1) in which Ar₁ is hydroxy substituted. A compound of formula(1) in which Ar₁ has a benzyloxy substituent is contacted withtrifluoroacetic acid. The reaction may be carried out using thioanisoleas a solvent. The reaction is carried out at temperatures of between 0°C. and 60° C. The reaction require from 1 to 24 hours. The product canbe isolated and purified by techniques well known in the art, such asevaporation, chromatography, and recrystallization.

For example, a modification may involve a compound of formula (1) iswhich R₁ is hydrogen is contacted with a slight molar excess of anappropriate alkylating agent. The reaction is carried out in thepresence of a slight molar excess of a suitable base, such as sodiumbicarbonate, potassium bicarbonate, diisopropylethyl amine or triethylamine. The reaction is carried out in a suitable solvent, such asacetonitrile, dimethylformamide, ethanol, zylene, toluene,tetrahydrofuran, tetrahydrofuran/water mixtures, or dimethyl sulfoxide.The reaction may be carried out in the presence of a suitable catalyst,such as potassium iodide, sodium iodide, tetrabutylammonium iodide,trimethylbenzylammonium iodide, tetraethylammonium iodide,tetrabutylammonium bromide, trimethylbenzylammonium bromide,tetraethylammonium bromide, tetrabutylammonium hydrogen sulfate,trimethylbenzylammonium hydrogen sulfate, tetraethylammonium hydrogensulfate, etc. The reaction is carried out at temperatures of from 20° C.to the reflux temperature of the solvent. The reaction generallyrequires from 1 to 48 hours. The product can be isolated and purified bytechniques well known in the art, such as extraction, evaporation,chromatography, and recrystallization.

In Scheme A, optional step g, a compound of formula (1) in which G₁ is--C(O)-- is reduced to give a compound of formula (1) in which G₁ is--CH₂ --.

For example, a compound of formula (1) in which G₁ is --C(O)-- iscontacted with a suitable reducing agent, such as diisobutylaluminumhydride, borane, borane dimethylsulfide complex, or litiumaluminumhydride with diisobutylaluminum hydride and boranedimethylsulfide complex being preferred. The reaction is carried out ina suitable solvent, such as tetrahydrofuran or toluene. The reaction iscarried out at temperatures of from -20° C. to the refluxing temperatureof the solvent. After an appropriate work-up, as is well known in theart, the work-up used depends on the products produced and the reducingreagent used, the product can be isolated and purified by techniqueswell known in the art, such as extraction, evaporation, chromatography,and recrystallization.

As is well known and appreciated in the art, Scheme A optional step fmay be carried out after optional steps c, e or f as required to preparethe compounds of formula (1), and further, that Scheme A optional stepsf and g may be carried out in any order which allows for the properincorporation of groups as desired in the final product of formula (1).

The following examples and preparations present typical syntheses asdescribed in Scheme A. These examples are understood to be illustrativeonly and are not intended to limit the scope of the invention in anyway.

EXAMPLE 1 Synthesis of(R)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazine##STR15## 2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2-phenyl-ethyl)-ethylamine

Scheme A, step a

Combine N-t-butoxycarbonyl-N-(2-oxo-ethyl)-2-phenyl-ethylamine (5.03 g,19.0 mmol) and (R)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylaminehydrochloride salt ((R)-tryptophan methyl ester hydrochloride salt) (4.9g, 19.42 mmol) in methanol (50 mL) and stir for 30 minutes. Add sodiumcyanoborohydride in solution (15.0 mL, 1M in THF, 15.0 mmol) and stirunder an inert atmosphere for 16.5 hours. Concentrate in vacuo to obtaina residue. Dilute the residue with ethyl acetate and extract with water.Separate the layers, dry the organic layer over MgSO₄, filter, andevaporate in vacuo. Chromatograph on silica gel eluting with 50% ethylacetate/hexane to give the title compound.

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2-phenyl-ethyl)-ethylaminehydrochloride disalt

Scheme A, step b

Combine 2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2-phenyl-ethyl)-ethylamine(1.64 g, 3.53 mmol) and dichloromethane (30 mL). Slowly pass hydrogenchloride gas through the solution for 20 minutes. Stir for 1 hour. Adddiethyl ether (150 mL) to form a solid. Filter and dry under vacuum togive the title compound. Elem. Anal. calculated for C₂₂ H₂₇ N₃ O₂.0.75H₂ O: C, 58.70; H, 6.98; N, 9.14. Found: C, 58.71; H, 6.98; N, 9.14.

(R)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazine

Scheme A, optional step c

Dissolve 2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2-phenyl-ethyl)-ethylaminehydrochloride disalt (3.80 g, 8.67 mmol) in toluene (40 mL). Addpyridine (20 mL) and heat to reflux for 23 hours. Cool to ambienttemperature. Dilute the reaction with ethyl acetate and extract withwater. Separate the layers, dry the organic layer over MgSO₄, filter,and evaporate in vacuo. Chromatograph on silica gel eluting sequentiallywith 50% ethyl acetate/hexane and 6% methanol/dichloromethane to givethe title compound.

(R)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazinehydrochloride salt

Dissolve (R)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazine(0.687 g, 1.50 mmol) in dichloromethane (20 mL). Cool to 0° C. Passhydrochloride gas through the solution for 15 minutes. Evaporate invacuo to obtain a residue. Dissolve the residue in hot ethanol (5 mL)and add diethyl ether. Cool and filter to give the title compound. Elem.Anal. calculated for C₂₁ H₂₃ N₃ O.HCl: C, 68.19; H, 6.54; N, 11.36.Found: C, 67.79; H, 6.73; N, 11.20. Specific rotation α!² _(D) ⁰ =+113°(c=1.00, DMSO).

EXAMPLE 2 Synthesis of(S)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazine##STR16## 2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2-phenyl-ethyl)-ethylamine

Scheme A, step a

Combine N-t-butoxycarbonyl-N-(2-oxo-ethyl)-2-phenyl-ethylamine (5.10 g,19.16 mmol) and (S)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylaminehydrochloride salt ((S)-tryptophan methyl ester hydrochloride salt)(4.90 g, 19.23 mmol) in methanol (50 mL) and stir for 10 minutes. Addsodium cyanoborohydride in solution (19.0 mL, 1M in THF, 19.0 mmol) andstir under an inert atmosphere for 18 hours. Concentrate in vacuo toobtain a residue. Dilute the residue with ethyl acetate and extract withwater. Separate the layers, dry the organic layer over MgSO₄, filter,and evaporate in vacuo. Chromatograph on silica gel eluting with 50%ethyl acetate/hexane to give the title compound.

2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2-phenyl-ethyl)-ethylaminehydrochloride disalt

Scheme A, step b

Combine 2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2-phenyl-ethyl)-ethylamine(4.77 g, 10 mmol) and diethyl ether (50 mL). Cool to 0° C. in anice-bath. Slowly pass hydrogen chloride gas through the solution for 30minutes. Stir for 4 hour at 0° C. Warm to ambient temperature and stirfor 1 hour. Evaporate in vacuo to give a residue. Dissolve the residuein methanol and triturate the residue with diethyl ether to form asolid. Filter and dry under vacuum to give the title compound. Elem.Anal. calculated for C₂₂ H₂₇ N₃ O₂.0.50 H₂ O: C, 59.06; H, 6.76; N,9.39. Found: C, 58.90; H, 7.01; N, 9.18.

(S)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazine

Scheme A, optional step c

Dissolve 2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2-phenyl-ethyl)-ethylaminehydrochloride disalt (3.12 g, 7.13 mmol) in toluene (40 mL). Addpyridine (20 mL) and heat to reflux for 15 hours. Cool to ambienttemperature. Dilute the reaction with ethyl acetate and extract withwater. Separate the layers, dry the organic layer over MgSO₄, filter,and evaporate in vacuo. Chromatograph on silica gel eluting sequentiallywith 50% ethyl acetate/hexane and 6% methanol/dichloromethane to givethe title compound.

(S)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazinehydrochloride salt

Dissolve (S)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazine(0.545 g, 1.64 mmol) in dichloromethane (20 mL). Cool to 0° C. Passhydrochloride gas through the solution for 15 minutes. Evaporate invacuo to obtain a residue. Triturate with diethyl ether to give a solid.Filter and dry in vacuo to give the title compound. Elem. Anal.calculated for C₂₁ H₂₃ N₃ O.HCl.0.8 H₂ O: C, 65.74; H, 6.70; N, 10.95.Found: C, 66.14; H, 6.96; N, 10.57. Specific rotation α!² _(D) ⁰ =-104°(c=1.00, DMSO).

EXAMPLE 3 Synthesis of (R)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine ##STR17## 2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-2- (4-benzyloxy)phenyl-ethyl!!-ethylamine

Scheme A, step a

Combine N-t-butoxycarbonyl-N-(2-oxo-ethyl)-2-4-benzyloxy)phenyl!-ethylamine (8.31 g, 22.49 mmol) and(R)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamine hydrochloride salt((R)-tryptophan hydrochloride salt) (5.46 g, 21.44 mmol) in methanol(100 mL) and stir for 30 minutes. Add sodium cyanoborohydride insolution (19.0 mL, 1M in THF, 19.0 mmol) and stir under an inertatmosphere for 24 hours. Concentrate in vacuo to obtain a residue.Dilute the residue with ethyl acetate and extract with water. Separatethe layers, dry the organic layer over MgSO₄, filter, and evaporate invacuo. Chromatograph on silica gel eluting sequentially with 30% ethylacetate/hexane and 50% ethyl acetate/hexane to give the title compound:R_(f) =0.55 (silica gel, 70% ethyl acetate/hexane). HRMS calculated forC₂₈ H₂₉ N₃ O₂ 572.3124. Found 572.3109.

2- (R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- 2-(4-benzyloxy)phenyl-ethyl!!-ethylamine hydrochloride disalt

Scheme A, step b

Combine 2-(R)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-2- (4-benzyloxy)phenyl-ethyl!!-ethylamine (6.00 g, 10.5 mmol) and 4Mhydrochloric acid in dioxane (40 mL). Allow to stir for 1 hour.Evaporate in vacuo to give the title compound.

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine

Scheme A, optional step c

Dissolve 2- (R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- 2-(4-benzyloxy)phenyl-ethyl!!-ethylamine hydrochloride disalt (5.49 g,10.08 mmol) in toluene (60 mL). Add pyridine (30 mL) and heat to refluxfor 16 hours. Cool to ambient temperature. Dilute the reaction withethyl acetate and extract with water. Separate the layers, dry theorganic layer over MgSO₄, filter, and evaporate in vacuo. Chromatographon silica gel eluting sequentially with 50% ethyl acetate/hexane and 6%methanol/dichloromethane to give the title compound: TLC R_(f) =0.44(silica gel, 10% methanol/dichloromethane). Elem. Anal. calculated forC₂₈ H₂₉ N₃ O₂.0.25 H₂ O: C, 75.74; H, 6.70; N, 9.46. Found: C, 75.54; H,6.55; N, 9.32.

EXAMPLE 4 Synthesis of (S)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine ##STR18## 2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-2- (4-benzyloxy)phenyl-ethyl!!-ethylamine

Scheme A, step a

Combine N-t-butoxycarbonyl-N-(2-oxo-ethyl)-2-4-benzyloxy)phenyl!-ethylamine (0.37 g, 1.0 mmol) and(S)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamine hydrochloride salt((S)-tryptophan hydrochloride salt) (0.25 g, 1.0 mmol) in methanol (10mL) and stir for 5 minutes. Add sodium cyanoborohydride in solution (0.8mL, 1M in THF, 0.8 mmol) and stir under an inert atmosphere for 24hours. Concentrate in vacuo to obtain a residue. Dilute the residue withethyl acetate and extract with water. Separate the layers, dry theorganic layer over MgSO₄, filter, and evaporate in vacuo. Chromatographon silica gel eluting with 5% methanol/dichloromethane to give the titlecompound: TLC R_(f) =0.62 (silica gel, 10% methanol/dichloromethane).

2- (S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- 2-(4-benzyloxy)phenyl-ethyl!!-ethylamine hydrochloride disalt

Scheme A, step b

Combine 2-(S)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-2- (4-benzyloxy)phenyl-ethyl!!-ethylamine (2.1 g, 3.67 mmol)and 4Mhydrochloric acid in dioxane (20 mL). Allow to stir for 1 hour.Evaporate in vacuo to give the title compound as a solid: TLC R_(f)=0.54 (silica gel, 85% chloroform, 10% methanol, 5% acetic acid).

(S)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine

Scheme A, optional step c

Dissolve 2- (S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- 2-(4-benzyloxy)phenyl-ethyl!!-ethylamine hydrochloride disalt (1.94 g,3.56 mmol) in toluene (33 mL). Add pyridine (11 mL) and heat to refluxfor 16 hours. Cool to ambient temperature. Dilute the reaction withethyl acetate and extract with water. Separate the layers, dry theorganic layer over MgSO₄, filter, and evaporate in vacuo. Chromatographon silica gel eluting sequentially with 50% ethyl acetate/hexane and 5%methanol/dichloromethane to give the title compound as a white solid:TLC R_(f) =0.42 (silica gel, 10% methanol/dichloromethane). Elem. Anal.calculated for C₂₈ H₂₉ N₃ O₂.0.25 H₂ O; C, 75.74; H, 6.70; N, 9.46.Found: C, 75.82; H. 6.66; N, 9.49.

EXAMPLE 5 Synthesis of(R)-3-(1H-Indol-3-ylmethyl)-1-(2,2-bis-phenyl-ethyl)-2-oxo-piperazine##STR19## 2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2,2-bis-phenyl-ethyl)!-ethylamine

Scheme A, step a

Combine N-t-butoxycarbonyl-N-(2-oxo-ethyl)-2,2-bis-phenyl!-ethylamine(0.22 g, 0.69 mmol) and (R)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylaminehydrochloride salt ((R)-tryptophan methyl ester hydrochloride salt)(0.20 g, 0.79 mmol) in methanol and stir for 10 minutes. Add sodiumcyanoborohydride in solution (0.55 mL, 1M in THF, 0.55 mmol) and stirunder an inert atmosphere for 24 hours. Concentrate in vacuo to obtain aresidue. Dilute the residue with ethyl acetate and extract with water.Separate the layers, dry the organic layer over MgSO₄, filter, andevaporate in vacuo. Chromatograph on silica gel eluting with 50% ethylacetate/hexane to give the title compound.

2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2,2-bis-phenyl-ethyl)!-ethylamine

Scheme A, step b

Combine 2-(R)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2,2-bis-phenyl-ethyl)!-ethylamine(0.22 g, 0.41 mmol) and dichloromethane (5 mL). Slowly pass hydrogenchloride gas through the solution for 30 minutes. Stir for 1 hour.Evaporate in vacuo to give a residue. Triturate the residue with diethylether and evaporate in vacuo to give a residue. Dry under vacuum to givethe title compound.

(R)-3-(1H-Indol-3-ylmethyl)-1-(2,2-bis-phenyl-ethyl)-2-oxo-piperazine

Scheme A, optional step c

Combine 2-(R)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2,2-bis-phenyl-ethyl)!-ethylamine(0.16 g, 0.31 mmol) and toluene (5 mL). Add pyridine (2.5 mL) and heatto reflux for 16 hours. Cool to ambient temperature. Concentrate thereaction mixture in vacuo to obtain a residue. Dilute the residue withethyl acetate and extract with water. Separate the layers, dry theorganic layer over MgSO₄, filter, and evaporate in vacuo. Chromatographon silica gel eluting with 6% methanol/dichloromethane to give the titlecompound: TLC R_(f) =0.37 (silica gel, 6% methanol/dichloromethane.

EXAMPLE 6

Synthesis of (R)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(hydroxy)phenyl!ethyl!!-2-oxo-piperazine ##STR20##

(R)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(hydroxy)phenyl!ethyl!!-2-oxo-piperazine

Scheme A, optional deprotection step f

Combine (R)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine (0.6 g, 1.36 mmol),thioanisole (8 mL), and trifluoroacetic acid (27 mL). Stir at ambienttemperature for 1 hour. Concentrate in vacuo. Chromatograph on silicagel eluting 5% methanol/dichloromethane to give the title compound: TLCR_(f) =0.39 (silica gel, 10% methanol/dichloromethane). Elem. Anal.calculated for C₂₁ H₂₃ N₃ O₂.0.75 H₂ O: C, 69.50; H, 6.80; N, 11.58.Found: C, 69.64; H, 6.81; N, 11.52.

EXAMPLE 7 Synthesis of (S)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(hydroxy)phenyl!ethyl!-2-oxo-piperazine ##STR21##(S)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(hydroxy)phenyl!ethyl!-2-oxo-piperazine

Scheme A, optional deprotection step f

Combine (S)-3-(1H-Indol-3-ylmethyl)-1- 2-4-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine (0.13 g, 0.3 mmol),thioanisole (1.76 mL), and trifluoroacetic acid (6 mL). Stir at ambienttemperature for 1 hour. Concentrate in vacuo. Chromatograph on silicagel eluting sequentially with 3% methanol/dichloromethane and 5%methanol/dichloromethane to give the title compound: TLC R_(f) =0.49(silica gel, 10% methanol/dichloromethane). HRMS calculated for C₂₁ H₂₃N₃ O₂ 349.1790. Found 349.1790.

PREPARATION 1 Synthesis of 3- (chloro)acetyl!-indole

According to the method of J. Bergman et al. Tet. 29, 971-976 (1973),combine indole (11.7 g, 100 mmol), pyridine (8.1 mL, 100 mmol), andtoluene (250 mL). Heat to 55° C. Add dropwise a solution of chloroacetylchloride (8 mL, 100 mmol) in toluene (10 mL). After 2 hours, cool toambient temperature. Dilute the reaction mixture with ethyl acetate andextract with water. Dry the organic layer over MgSO₄, filter andevaporate in vacuo to give a residue. Recrystallize the residue fromethanol to give the title compound.

EXAMPLE 8 Synthesis of (R)-3-(1H-Indol-3-ylmethyl)-4-2-(1H-indol-3-yl)-2-oxo-ethyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine##STR22## (R)-3-(1H-Indol-3-ylmethyl)-4-2-(1H-indol-3-yl)-2-oxo-ethyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine

Scheme A, optional modification step f

Dissolve (R)-3-(1H-indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazine(0.50 g, 1.50 mmol) in acetonitrile (15 mL). Add 3-(chloro)acetyl!-indole (0.33 g, 1.70 mmol), potassium bicarbonate (0.60g, 6.0 mmol), and tetrabutylammoniun iodide (0.060 g, 0.16 mmol). Heatto reflux for 2 hours. Evaporate in vacuo to obtain a residue. Dissolvethe residue in ethyl acetate and extract with water. Dry the organiclayer over MgSO₄, filter, and evaporate in vacuo to give a residue.Chromatograph on silica gel eluting sequentially with 50% ethylacetate/hexane and 6% methanol/dichloromethane. Recrystallize fromchloroform to give the title compound was a solid: TLC R_(f) =0.55(silica gel, 10% methanol/dichloromethane). Elem. Anal. calculated forC₃₁ H₃₀ N₄ O₂ : C, 75.89; H, 6.16; N, 11.42. Found: C, 75.37; H, 6.27;N, 11.12. HRMS calculated (M+H) 491.2447. Found 491.2447.

EXAMPLE 9 Synthesis of (R)-3-(1H-Indol-3-ylmethyl)-4-2-(1H-indol-3-yl)-2-oxo-ethyl!-1-(2,2-bis-phenyl-ethyl)-2-oxo-piperazine##STR23## (R)-3-(1H-Indol-3-ylmethyl)-4-2-(1H-indol-3-yl)-2-oxo-ethyl!-1-(2,2-bis-phenyl-ethyl)-2-oxo-piperazine

Scheme A, optional modification step f

Dissolve(R)-3-(1H-indol-3-ylmethyl)-1-(2,2-bis-phenyl-ethyl)-2-oxo-piperazine(0.50 g, 1.22 mmol) in acetonitrile (15 mL). Add 3-(chloro)acetyl!-indole (0.26 g, 1.34 mmol), potassium bicarbonate (0.50g, 5.0 mmol), and tetrabutylammoniun iodide (0.055 g, 0.15 mmol). Heatto reflux for 2 hours. Evaporate in vacuo to obtain a residue. Dissolvethe residue in ethyl acetate and extract with water. Dry the organiclayer over MgSO₄, filter, and evaporate in vacuo to give a residue.Chromatograph on silica gel eluting with 50% ethyl acetate/hexane.Recrystallize from chloroform to give the title compound as a solid.HRMS calculated for C₃₆ H₃₄ N₄ O₂ 567.2760. Found 567.2733.

EXAMPLE 10 Synthesis of (R)-3-(1H-Indol-3-ylmethyl)-4-2-(1H-indol-3-yl)-2-oxo-ethyl!-1- 2-4-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine ##STR24##(R)-3-(1H-Indol-3-ylmethyl)-4- 2-(1H-indol-3-yl)-2-oxo-ethyl!-1- 2-4-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine

Scheme A, optional modification step f

Combine (R)-3-(1H-indol-3-ylmethyl)-4- 2-(1H-indol-3-yl)-2-oxo-ethyl!-1-2- 4-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine (0.67 g, 1.53 mmol), 3-(chloro)acetyl!-indole (0.31 g, 1.63 mmol), and diisopropylethylamine(0.31 mL, 1.84 mmol) in acetonitrile (30 mL). Heat to reflux for 16hours. Evaporate in vacuo. Chromatograph on silica gel elutingsequentially with 50% ethyl acetate/hexane and 3%methanol/dichloromethane. Recrystallize from chloroform to give thetitle compound as a white solid: TLC R_(f) =0.67 (silica gel, 10%methanol/dichloromethane); mp; 175°-176° C. Elem. Anal. calculated forC₃₁ H₃₀ N₄ O₂.0.25H₂ O: C, 75.20; H, 6.21; N, 11.32. Found: C, 75.20; H,6.16; N, 11.33.

EXAMPLE 11 Synthesis of (R)-3-(1H-Indol-3-ylmethyl)-4-2-(1H-indol-3-yl)-2-oxo-ethyl!-1- 2-4-(hydroxy)phenyl)ethyl!-2-oxo-piperazine ##STR25##(R)-3-(1H-Indol-3-ylmethyl)-4- 2-(1H-indol-3-yl)-2-oxo-ethyl!-1- 2-4-(hydroxy)phenyl!ethyl!-2-oxo-piperazine

Scheme A, optional deprotection step f

Combine (R)-3,4-bis-(1H-indol-3-ylmethyl)-4-2-(1H-indol-3-yl)-2-oxo-ethyl!-1-2-4-(benzyloxy)phenyl!ethyl!-2-oxo-piperazine (0.19 g, 0.32 mmol),thioanisole (1.90 mL), and trifluoroacetic acid (6 mL). Stir at ambienttemperature for 1 hour. Concentrate in vacuo. Chromatograph on silicagel eluting with 5% methanol/dichloromethane to give the title compound:TLC R_(f) =0.57 (silica gel, 10% methanol/dichloromethane. HRMScalculated for C₃₀ H₃₀ N₄ O₃ 507.2396. Found 507.2392.

EXAMPLE 12 Synthesis of (R)-3-(1H-Indol-3-ylmethyl)-4-(S)-pyroglutamoyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine ##STR26##(R)-3-(1H-Indol-3-ylmethyl)-4-(S)-pyroglutamoyl!-2-oxo-ethyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine

Scheme A, optional modification step f

Dissolve (R)-3-(1H-indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazine(0.50 g, 1.50 mmol) in dimethylformamide (15 mL). Add (S)-pyroglutamicacid (0.22 g, 1.67 mmol), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimidehydrochloride (0.32 g, 1.67 mmol), and 1-hydroxybenzotriazole hydrate(0.23 g, 1.67 mmol). After 24 hours, pour the reaction mixture intoethyl acetate. Extract with water and saturated aqueous sodium chloridesolution. Dry the organic layer over MgSO₄, filter, and evaporate invacuo to give a residue. Chromatograph the residue on silica gel elutingwith 6% methanol/dichloromethane to give a residue. Recrystallize theresidue obtained by chromatography from ethanol to give the titlecompound. Elem Anal. calculated for C₂₆ H₂₈ N₄ O₃.0.25H₂ O: C, 69.55; H,6.40; N, 12.48. Found: C, 69.46, H, 6.48; N, 12.75.

EXAMPLE 13 Synthesis of (R)-3-(1H-Indol-3-ylmethyl)-4-2-phenyl-2-oxo-ethyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine ##STR27##(R)-3-(1H-Indol-3-ylmethyl)-4-2-phenyl-2-oxo-ethyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine

Scheme A, optional modification step f

Prepare by a method similar to Example 8 using(R)-3-(1H-indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazine andα-chloroacetophenone to give the title compound.

EXAMPLE 14 Synthesis of (R)-3-(1H-Indol-3-ylmethyl)-4-(phenyl)methyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine ##STR28##(R)-3-(1H-Indol-3-ylmethyl)-4-((phenyl)methyl!-1-(2-phenyl-ethyl)-2-oxo-piperazine

Scheme A, optional modification step f

Dissolve (R)-3-(1H-indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazine(0.50 g, 1.50 mmol) in tetrahydrofuran (15 mL). Add benzyl bromide (1.70mmol), and potassium carbonate (6.0 mmol). Heat to reflux for 24 hours.Evaporate in vacuo to obtain a residue. Dissolve the residue in ethylacetate and extract with water. Dry the organic layer over MgSO₄,filter, and evaporate in vacuo to give a residue. Chromatograph onsilica gel to give the title compound

EXAMPLE 15 Synthesis of(S)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-piperazine ##STR29##(S)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-piperazine

Scheme A, step a

Combine lithiium aluminumhydride (100 mmol) and tetrahydrofuran (75 ml).Add (S)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazine (25mmol) portionwise. Heat to reflux. After 24 hours, cool to ambienttemperature. Carefully add water (3.8 mL), 15% aqueous sodium hydroxidesolution (3.8 mL), and water (10.5 mL). Stir vigourously for 1 hour.Filter, rinse the filter cake repeatedly with tetrahydrofuran.Concentrate the filtrate in vacuo to obtain a residue. Chromatograph theresidue to give the title compound.

A general synthetic procedure is set forth in Scheme B for preparing thealdehydes of formula (4). The reagents and starting materials arereadily available to one of ordinary skill in the art. In Scheme B, allsubstituents, unless otherwise indicated, are as previously defined.##STR30##

In Scheme B, step a, an appropriate arylethylamine of structure (7) orsalt thereof is protected with a suitable carbamate forming reagent togive a carbamate protected arylethylamine of structure (8).

An appropriate arylethylamine of structure (7) is one in which Ar₁ andR₃ are as desired in the final compound of formula (1), or can bedeprotected to give a Ar₁ and R₃ as desired in the final compound offormula (1).

For example, an appropriate arylethylamine of structure (7) or a saltthereof is contacted with a suitable carbamate forming reagent, such asmethyl chloroformate, ethylchloroformate, benzyl chloroformate,di-t-butyl dicarbonate, etc. When a salt appropriate arylethylamine ofstructure (7) is used the reaction is carried out in the presence of anequimolar amount of a suitable base, such as triethylamine,N-methylmorpholine, or diisopropylethylamine. The reaction is carriedout in a suitable solvent, such as tetrahydrofuran, dimethylformamide,ethyl acetate, or dimethylformamide/ethyl acetate mixtures. Thereactions are generally carried out at ambient temperature. The productcan be isolated and purified by techniques well known in the art, suchas extraction, evaporation, chromatography, and recrystallization.

In Scheme B, optional step b, a substituent on R₃ or Ar₁ of a carbamateprotected arylethylamine of structure (8) may be converted to a group asis desired in the final product of formula (1) to give a carbamatearylethylamine of structure (9).

For example, a carbamate protected arylethylamine of structure (8) inwhich Ar₁ has a hydroxy substituent is contacted with a suitablealkylating reagent, such as iodomethane, bromoethane, bromopropane,chloropropane, bromobutane, chlorobutane, benzyl bromide, benzylchloride, 4-methoxybenzyl chloride, etc. The reaction is carried out ina suitable solvent, such as tetrahydrofuran, dimethylformamide, ordichloromethane. The reaction is carried out in the presence of asuitable base, such as triethylamine, sodium carbonate, ordiisopropylethylamine. The reactions are generally carried out atambient temperature and generally requires form 1 to 48 hours. Theproduct can be isolated and purified by techniques well known in theart, such as extraction, evaporation, chromatography, andrecrystallization.

Alternately, such a reaction may be carried out under phase transfercatalysis, using a suitable catalyst, such as tetrabutylammoniumbromide, tetraethylammonium chloride, or tetrabutylammonium hydrogensulfate, tetraethylammonium bromide, trimethylbenzylammonium bromide,etc. The reaction is carried out in a suitable solvent system, such asdichloromethane/water, toluene/water, or ethyl acetate water. Thetwo-phase reaction is carried out in the presence of a suitable base,such as sodium hydroxide or potassium hydroxide. The reactions arecarried out at ambient temperature. The reaction generally requires form1 to 48 hours. The product can be isolated and purified by techniqueswell known in the art, such as extraction, evaporation, chromatography,and recrystallization.

In Scheme B, step c, a carbamate protected arylethylamine of structure(9) is allylated to give a carbamate protected allylamine of structure(10).

For example, a carbamate protected arylethylamine of structure (9) iscontacted with an excess of allyl bromide or allyl chloride. Thereaction is carried out in the presence of a suitable base, such assodium hydride, n-butyllithium, or lithium diisopropylamide. Thereaction is carried out in a suitable solvent, such as tetrahydrofuran,dimethylformamide, or tetrahydrofuran/dimethylformamide mixtures. Thereaction is carried out at temperature of from 0° C. to the refluxtemperature of the solvent. The reaction may require additional allylbromide or allyl chloride after 1 to 24 hours in order to increase theyield of allylated product. The reaction generally requires from 12 to72 hours. The product can be isolated and purified by techniques wellknown in the art, such as extraction, evaporation, chromatography, andrecrystallization.

In Scheme B, step d, a carbamate protected allylamine of structure (10)is converted to an aldehyde of structure (4). A carbamate protectedallylamine of structure (10) may be converted to an aldehyde ofstructure (4) by either; ozonolysis in the presence of methanol followedby a reductive work-up, or an osmium tetraoxide mediated formation of anintermediate diol followed by oxidative cleavage with lead tetraacetate.

For example, a carbamate protected allylamine of structure (10) iscontacted with ozone in the presence of methanol. The reaction iscarried out in a suitable solvent, such as dichloromethane. The reactionis carried out a at temperature of from about -100° C. to about -60° C.,with about -70° C. being preferred. The reaction is worked-upreductively by the addition of a suitable reducing agent, such astributylphosphine or dimethylsulfide. The product may be isolated byevaporation and may be used without further purification. The productmay be purified by techniques well known in the art, such aschromatography and recrystallization.

Alternatively, for example, a carbamate protected allylamine ofstructure (10) is contacted with osmium tetraoxide to give anintermediate diol. The reaction may be carried out using a 0.01 to 0.05molar equivalents of osmium tetraoxide and a slight molar excess of anoxidant, such as N-methylmorpholine-N-oxide or sodium meta-periodate.The reaction is carried out in a solvent, such as acetone/watermixtures. The reaction is carried out at ambient temperature andgenerally requires from 12 to 48 hours. The reaction mixture is added toa saturated solution of sodium bisulfite or sodium thiosulfate and theintermediate diol is isolated by extraction and evaporation and usedwithout further purifications. The intermediate dial is contacted with aslight molar excess of lead tetraacetate. The lead tetraacetate reactionis carried out in a solvent, such as chloroform. The reaction isgenerally carried out at ambient temperature and generally requires from30 minutes to 8 hours. The product may be isolated by extraction andevaporation and may be used without further purification. The productmay be purified by techniques well known in the art, such aschromatography and recrystallization.

The following examples and preparations present typical syntheses asdescribed in Scheme B. These preparations are understood to beillustrative only and are not intended to limit the scope of theinvention in any way.

PREPARATION 2 Synthesis ofN-t-Butoxycarbonyl-N-(2-oxo-ethyl)-2-phenyl-ethylamineN-t-Butoxycarbonyl-2-phenyl-ethylamine

Scheme B, step a

Combine phenethylamine hydrochloride (15.8 g, 100 mmol) andN-methylmorpholine (11 mL, 100 mmol) in dichloromethane (100 mL). Coolto 0° C. Add dimethylaminopyridine (1.0 g, 8.2 mmol) and di-t-butyldicarbonate (22.0 g, 100 mmol) and allow to stir at 0° C. for 1 hour.Warm to ambient temperature and stir for 18 hours. Evaporate in vacuo togive a residue. Dilute the residue with ethyl acetate and extract withwater. Dry the organic layer over MgSO₄, filter, and evaporate in vacuoto give the title compound.

N-t-Butoxycarbonyl-N-allyl-2-phenyl-ethylamine

Scheme B, step c

Combine N-t-butoxycarbonyl-2-phenyl-ethylamine (22.1 g, 100 mmol) andTHF (100 mL) under an inert atmosphere. Cool to 0° C. in an ice-bath.Add portionwise sodium hydride (0.206 g, 110 mmol) and allow to stiruntil hydrogen evolution ceases. Add allyl bromide (9.50 mL, 110 mmol)and warm to ambient temperature. Cool again to 0° C. in an ice-bath. Addsodium hydride (0.92 g, 40 mmol) and allow to stir until hydrogenevolution ceases. Add allyl bromide (3.0 mL, 35.0 mmol) and heat toreflux for 18 hours. Cool to ambient temperature. Add a saturatedaqueous solution of ammonium chloride (200 mL) and extract with ethylacetate. Dry the organic layer over MgSO₄, filter, and evaporate invacuo. Chromatograph eluting sequentially with hexane and 10% ethylacetate/hexane to give the title compound.

N-t-Butoxycarbonyl-N-(2-oxo-ethyl)-2-phenyl-ethylamine

Scheme B, step d

Dissolve N-t-butoxycarbonyl-N-allyl-2-phenyl-ethylamine (7.88 g, 21.44mmol) in dichloromethane (200 mL) and methanol (5 mL). Cool to -78° C.Pass ozonized oxygen through the solution until a persistent light bluecolor is obtained. Pass nitrogen through the solution until the bluecolor dissipates. Add dimethyl sulfide (20 mL). Allow the reactionmixture to warm to ambient temperature and stir for 5 hours. Concentratein vacuo to obtain a residue. Dilute the residue with ethyl acetate andextract with water. Separate the layers, dry the organic layer overMgSO₄, filter, and evaporate in vacuo to give the title compound.

PREPARATION 3 Synthesis of N-t-Butoxycarbonyl-N-(2-oxo-ethyl)-2-(4-benzyloxy)-phenyl!-ethylamine N-t-Butoxycarbonyl-2-(4-hydroxy-phenyl)!-ethylamine

Scheme B, step a

Combine 2- (4-hydroxy)-phenyl!-ethylamine hydrochloride (3.47 g, 20.0mmol), diisopropylethylamine (3.48 mL, 20.0 mmol), and di-t-butyldicarbonate (4.36 g, 20.0 mmol) in 1/1 DMF/ethyl acetate (40 mL). Stirat ambient temperature for 2 hours. Dilute with ethyl acetate andextract with water. Dry the organic layer over MgSO₄, filter, andevaporate in vacuo to give the title compound: TLC R_(f) =0.32 (silicagel, 30% ethyl acetate/hexane).

N-t-Butoxycarbonyl-2- (4-benzyloxy)-phenyl!-ethylamine

Scheme B, optional step b

Combine N-t-butoxycarbonyl-2- (4-hydroxy)-phenyl!-ethylamine (2.93 g,12.34 mmol), sodium hydroxide (0.99 g, 24.7 mmol), tetrabutylammoniumbromide (0.397 g, 1.23 mmol), and benzyl bromide (1.48 g, 12.3 mmol) inwater (60 mL) and dichloromethane (60 mL). Stir for 20 hours. Add sodiumhydroxide (0.99 g, 24.7 mmol) water (40 mL) and benzyl bromide (0.71 g,6.2 mmol) and stir for 5 hours. Add benzyl bromide (0.71 g, 6.2 mmol)and stir for 20 hours more. Extract the reaction mixture with water. Drythe organic layer over MgSO₄, filter, and evaporate in vacuo.Chromatograph eluting sequentially hexane and 10% ethyl acetate/hexaneto give the title compound as an oil.

N-t-Butoxycarbonyl-N-allyl-2- (4-benzyloxy)-phenyl!-ethylamine

Scheme B, step c

Combine N-t-butoxycarbonyl-2-(4-benzyloxy-phenyl)-ethylamine (1.27 g,3.90 mmol) and DMF (8 mL) and THF (70 mL) under an inert atmosphere.Cool to 0° C. in an ice-bath. Add sodium hydride (0.206 g, 8.58 mmol)and allow to stir until hydrogen evolution ceases. Add allyl bromide(2.02 mL, 23.4 mmol) and heat to reflux. Cool again to 0° C. in anice-bath. Add sodium hydride (0.10 g, 4.4 mmol) and allow to stir untilhydrogen evolution ceases. Add allyl bromide (1.0 mL, 12.7 mmol) andheat to reflux. Add a saturated aqueous solution of ammonium chloride(200 mL) and extract with dichloromethane. Dry the organic layer overMgSO₄, filter, and evaporate in vacuo. Chromatograph elutingsequentially with hexane and 10% ethyl acetate/hexane to give the titlecompound. R_(f) =0.72 (silica gel, 30% ethyl acetate/hexane)

N-t-Butoxycarbonyl-N-(2-oxo-ethyl)-2- (4-benzyloxy)-phenyl!-ethylamine

Scheme B, step d

Dissolve N-t-butoxycarbonyl-N-allyl-2- (4-benzyloxy)-phenyl!-ethylamine(7.88 g, 21.44 mmol) in dichloromethane (180 mL) and methanol (20 mL)containing pyridine (0.08 mL). Cool to -78° C. Pass ozonized oxygenthrough the solution until a persistent light blue color is obtained.Pass nitrogen through the solution until the blue color dissipates. Adddimethyl sulfide (34 mL). Allow the reaction mixture to warm to ambienttemperature and stir for 16 hours. Concentrate in vacuo to obtain aresidue. Dilute the residue with ethyl acetate and extract with water.Separate the layers, dry the organic layer over MgSO₄, filter, andevaporate in vacuo to give the title compound: TLC R_(f) =0.32 (silicagel, 30% ethyl acetate/hexane).

PREPARATION 4 Synthesis ofN-t-Butoxycarbonyl-N-(2-oxo-ethyl)-2,2-bis-phenyl-ethylamineN-t-Butoxycarbonyl-2,2-bis-phenyl-ethylamine

Scheme B, step a

Combine 2,2-bis-phenyl-ethylamine (20.0 g, 100.0 mmol) anddichloromethane (200 mL) and cool in an ice-bath to 0° C. Adddimethylaminopyridine (1.0 g, 8.2 mmol) and di-t-butyl dicarbonate (22.0g, 100.0 mmol). After the addition is complete warm to ambienttemperature for 5 hours. Evaporate in vacuo to give a residue. Dissolvethe residue in ethyl acetate and extract with 0.1M hydrochloric acidsolution, water and saturated sodium chloride solution. Separate theorganic layer and dry over MgSO₄, filter and evaporate in vacuo toobtain a residue. Chromatograph the residue on silica gel eluting with10% ethyl acetate/hexane to give the title compound.

N-t-Butoxycarbonyl-N-allyl-2,2-bis-phenyl-ethylamine

Scheme B, step c

Combine N-t-butoxycarbonyl-2,2-bis-phenyl-ethylamine (2.0 g, 7.73 mmol)and tetrahydrofuran (20 mL) and cool in a dry-ice/acetone bath to -78°C. Slowly, add n-butyllithium (4.4 mL, 1.6M in hexane, 7.04 mmol) andallow to stand for 30 minutes. Add allyl bromide (0.7 mL, 8.09 mmol)maintaining the temperature at -78° C. Warm to ambient temperature andallow to stand for 1.5 hour and then heat to reflux for 5 hours. Cool toambient temperature and allow to stand for 18 hours. Extract thereaction mixture with a saturated ammonium chloride solution andseparate the layers. Extract the aqueous layer with diethyl ether andcombine the organic layers. Extract the combine organic layer with waterand saturated sodium chloride solution. Separate the organic layer anddry over MgSO₄, filter and evaporate in vacuo to obtain a residue.Chromatograph the residue on silica gel eluting with 5% ethylacetate/hexane to give the title compound.

N-t-Butoxycarbonyl-N-(2-oxo-ethyl)-2,2-bis-phenyl-ethylamine

Scheme B, step d

Combine N-t-butoxycarbonyl-N-allyl-2,2-bis-phenyl-ethylamine (0.23 g,0.68 mmol) and dichloromethane (10 mL) and methanol (0.5 mL). Cool the-78° C. Pass ozonized oxygen through the solution until a persistentlight blue color is obtained. Pass nitrogen through the solution untilthe blue color dissipates. Add dimethyl sulfide (2.0 mL). Allow thereaction mixture to warm to ambient temperature and stir for 5.5 hours.Concentrate in vacuo to obtain a residue. Dilute the residue with ethylacetate and extract with water. Separate the layers, dry the organiclayer over MgSO₄, filter, and evaporate in vacuo to give the titlecompound.

The tachykinins are a class of neuropeptides which share a commonC-terminus sequence, Phe-Xaa-Gly-Leu-Met-NH₂. The tachykinins are widelydistributed in the peripheral and central nervous systems where theybind to at least three receptors types. The NK₁, NK₂, and NK₃ receptorsare defined by the preferred binding affinity of substance P, neurokininA (NKA), and neurokinin B (NKB), respectively.

The use of tachykinin antagonists is indicated as therapy for a varietyof tachykinin-mediated diseases and conditions including: cystitis;bronchodilation; hypersensitivity reactions; the treatment of pain;peripheral neuropathy; post-herpetic neuralgia; adverse immunologicalreactions; respiratory diseases, such as asthma, bronchitis, cough,rhinitis, and allergies and the like; opthalmic diseases, such asconjuctivitis and vernal conjuctivitis; cutaneous diseases, such ascontact dermatitis, atopic dermatitis, and urticaria; inflammatorydiseases, such as rheumatoid arthritis and osteoarthritis, and the like;gastrointestinal conditions, such as Crohn's disease, emesis, andulcerative colitis; conditions due to vasodilation, such as angina andmigraine; and central nervous system diseases and conditions, such asanxiety, depression, psychosis, schizophrenia, dementia.

It is understood that tachykinin-mediated diseases and conditions arethose diseases and conditions in which the tachykinins are involved,either in whole or in part, in their clinical manifestation(s).Moreover, the tachykinins involvement is not necessarily causative of aparticular tachykinin-mediated disease and condition. Tachykininantagonists are useful in controlling or providing therapeutic relief ofthose tachykinin-mediated diseases and conditions.

The present invention provides new and useful tachykinin antagonists offormula (1) or stereoisomers or pharmaceutically acceptable saltsthereof. Particularly, the present invention provides compounds offormula (1) which are NK₂ receptor antagonists.

In a further embodiment, the present invention provides a method oftreating tachykinin-mediated diseases and conditions in a patient inneed thereof comprising administering to said patient a therapeuticallyeffective amount of a compound of formula (1). Various diseases andconditions described to be treated herein, are well known andappreciated by those skilled in the art. It is also recognized that oneskilled in the art may affect the associated diseases and conditions bytreating a patient presently afflicted with the diseases or conditionsor by prophylactically treating a patient afflicted with the diseases orconditions with a therapeutically effective amount of the compounds offormula (1).

As used herein, the term "patient" refers to a warm blooded animal suchas a mammal which is afflicted with a particular tachykinin-mediateddisease or condition. It is understood that guinea pigs, dogs, cats,rats, mice, horses, cattle, sheep, and humans are examples of animalswithin the scope of the meaning of the term.

As used herein, the term "therapeutically effective amount" of acompound of formula (1) refers to an amount which is effective incontrolling tachykinin-mediated diseases and conditions. The term"controlling" is intended to refer to all processes wherein there may bea slowing, interrupting, arresting, or stopping of the progression ofthe diseases and conditions described herein, but does not necessarilyindicate a total elimination of all disease and condition symptoms, andis intended to include prophylactic treatment of the tachykinin-mediateddiseases and conditions.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use ofconventional techniques and by observing results obtained underanalogous circumstances. In determining the therapeutically effectiveamount, the dose, a number of factors are considered by the attendingdiagnostician, including, but not limited to: the species of mammal; itssize, age, and general health; the specific disease involved; the degreeof or involvement or the severity of the disease; the response of theindividual patient; the particular compound administered; the mode ofadministration; the bioavailability characteristic of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

A therapeutically effective amount of a compound of formula (1) isexpected to vary from about 0.1 milligram per kilogram of body weightper day (mg/kg/day) to about 100 mg/kg/day. Preferred amounts are ableto be determined by one skilled in the art.

In effecting treatment of a patient afflicted with tachykinin-mediateddiseases and conditions described above, a compound of formula (1) canbe administered in any form or mode which makes the compoundbioavailable in an effective amount, including oral and parenteralroutes. For example, compounds of formula (1) can be administeredorally, by inhalation of an aerosol or dry powder, subcutaneously,intramuscularly, intravenously, transdermally, intranasally, rectally,topically, and the like. Oral or inhalation administration is generallypreferred for treatment of respiratory diseases and conditions, e.g.asthma. One skilled in the art of preparing formulations can readilyselect the proper form and mode of administration depending upon theparticular characteristics of the compound selected, the disease orcondition to be treated, the stage of the disease or condition, andother relevant circumstances. (Remington's Pharmaceutical Sciences, 18thEdition, Mack Publishing Co. (1990)).

The compounds of the present invention can be administered alone or inthe form of a pharmaceutical composition in combination withpharmaceutically acceptable carriers or excipients, the proportion andnature of which are determined by the solubility and chemical propertiesof the compound selected, the chosen route of administration, andstandard pharmaceutical practice. The compounds of the presentinvention, while effective themselves, may be formulated andadministered in the form of their pharmaceutically acceptable salts,such as acid addition salts or base addition salts, for purposes ofstability, convenience of crystallization, increased solubility and thelike.

In another embodiment, the present invention provides pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof formula (1) in admixture or otherwise in association with one or morepharmaceutically acceptable carriers or excipients.

The pharmaceutical compositions are prepared in a manner well known inthe pharmaceutical art. The carrier or excipient may be a solid,semi-solid, or liquid material which can serve as a vehicle or mediumfor the active ingredient. Suitable carriers or excipients are wellknown in the art. The pharmaceutical composition may be adapted fororal, inhalation, parenteral, or topical use and may be administered tothe patient in the form of tablets, capsules, aerosols, inhalants,suppositories, solution, suspensions, or the like.

The compounds of the present invention may be administered orally, forexample, with an inert diluent or with an edible carrier. They may beenclosed in gelatin capsules or compressed into tablets. For the purposeof oral therapeutic administration, the compounds may be incorporatedwith excipients and used in the form of tablets, troches, capsules,elixirs, suspensions, syrups, wafers, chewing gums and the like. Thesepreparations should contain at least 4% of the compound of the presentinvention, the active ingredient, but may be varied depending upon theparticular form and may conveniently be between 4% to about 70% of theweight of the unit. The amount of the compound present in compositionsis such that a suitable dosage will be obtained. Preferred compositionsand preparations according to the present invention may be determined bysomeone skilled in the art.

The tablets, pills, capsules, troches and the like may also contain oneor more of the following adjuvants: binders such as microcrystallinecellulose, gum tragacanth or gelatin; excipients such as starch orlactose, disintegrating agents such as alginic acid, Primogel, cornstarch and the like; lubricants such as magnesium stearate or Sterotex;glidants such as colloidal silicon dioxide; and sweetening agents suchas sucrose or saccharin may be added or a flavoring agent such aspeppermint, methyl salicylate or orange flavoring. When the dosage unitform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier such as polyethylene glycol or a fatty oil. Otherdosage unit forms may contain other various materials which modify thephysical form of the dosage unit, for example, as coatings. Thus,tablets or pills may be coated with sugar, shellac, or other entericcoating agents. A syrup may contain, in addition to the presentcompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors. Materials used in preparing these variouscompositions should be pharmaceutically pure and non-toxic in theamounts used.

For the purpose of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of acompound of the invention, but may be varied to be between 0.1 and about50% of the weight thereof. The amount of the compound of formula (1)present in such compositions is such that a suitable dosage will beobtained. Preferred compositions and preparations are able to bedetermined by one skilled in the art.

The compounds of the present invention may also be administered byinhalation, such as by aerosol or dry powder. Delivery may be by aliquefied or compressed gas or by a suitable pump system which dispensesthe the compounds of the present invention or a formulation thereof.Formulations for administration by inhalation of compounds of formula(1) may be delivered in single phase, bi-phasic, or tri-phasic systems.A variety of systems are available for the administration by aerosol ofthe compounds of formula (1). Dry powder formulations are prepared byeither pelletizing or milling the compound of formula (1) to a suitableparticle size or by admixing the pelletized or milled compound offormula (1) with a suitable carrier material, such as lactose and thelike. Delivery by inhalation includes the necessary container,activators, valves, subcontainers, and the like. Preferred aerosol anddry powder formulations for administration by inhalation can bedetermined by one skilled in the art.

The compounds of the present invention may also be administeredtopically, and when done so the carrier may suitably comprise asolution, ointment or gel base. The base, for example, may comprise oneor more of the following: petrolatum, lanolin, polyethylene glycols, beewax, mineral oil, diluents such as water and alcohol, and emulsifiersand stabilizers. Topical formulations may contain a concentration of theformula (1) or its pharmaceutical salt from about 0.1 to about 10% w/v(weight per unit volume).

The solutions or suspensions may also include one or more of thefollowing adjuvants: sterile diluents such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl paraben; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylene diaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampules, disposable syringesor multiple dose vials made of glass or plastic.

One skilled in the art can determine the NK₁ receptor and NK₂ receptoraffinity in vitro as follows. The NK₁ receptor affinity of tachykininantagonists is evaluated in guinea pig lungs (Keystone Biologicals,Cleveland, Ohio) and affinity for the NK₂ receptor is evaluated inHSKR-1 cells (which are mouse 3T3 fibroblasts expressing the humanjejunal NK₂ receptor). Tissues or cells are homogenized with a Polytronin 15 volumes of 50 mM Tris-HCl buffer (pH 7.4, 4° C.) and centrifuged.The pellet is resuspended in Tris-HCl buffer and is centrifuged; thepellet is washed twice by resuspension. The final pellet is resuspendedat a concentration of 40 mg/ml for tissues and 20 mg/ml for cells inincubation buffer and remains at room temperature for at least 15 minprior to use. Receptor binding is initiated by addition of 250 ulmembrane preparation in duplicate to 0.1 nM of the followingradioligands; ¹²⁵ I-Bolton Hunter Lys-3 labeled substance P and ¹²⁵iodohistidyl-1-neurokinin A; in a final volume of 500 ul of buffercontaining 50 mM Tris-HCl (pH 7.4 at room temperature), 0.1% bovineserum albumin, 2 mM MnCl₂, 40 ug/ml bacitracin, 4 μg/ml leupeptin andchymostatin, 10 μM thiorphan and various doses of the putativetachykinin antagonists. Incubations are performed at room temperaturefor 90 min (NK₁ receptor assays) or 2 hr (NK₂ receptor assay); bindingis terminated by addition of 50 mM Tris-HCl buffer (pH 7.4, 4° C.) andfiltration under vacuum through GF/B filters presoaked with 0.1%polyethyleneimine (NK₁ receptor assays) or 0.5% bovine serum albumin(NK₂ receptor assay). Filter bound radioactivity is quantitated in agamma counter. Nonspecific binding is defined as binding in the presenceof 1 μM substance P or neurokinin A. Specific binding is calculated bysubtracting nonspecific binding from total binding. Competition ofiodinated SP or NKA binding by test compounds or standards is expressedas a percentage of this maximum binding. IC₅₀ values (concentrationrequired to inhibit 50% of receptor binding) are generated for each ofthe test compounds by nonlinear regression using an iterative curvefitting program (GraphPAD Inplot, San Diego, Calif.).

One skilled in the art can also determine the NK₁ receptor and NK₂receptor affinity in vitro as follows. Tachykinin-mediatedphosphatidylinositol (PI, inositol phosphate) accumulation is measuredin UC11 or SKLKB82#3 cells in the presence and absence of NK₁ or NK₂receptor antagonists, respectively. Tissues are incubated inKrebs-Henseleit buffer at 37° C. with 95% O₂ -5% CO₂ gassing. Tissuesare then incubated with fresh buffer containing 100 μCi of myo- 2-³H(N)!inositol at 37° C. for 60 min with gentle gassing. After washingtwice in 5 ml room temperature buffer containing 10 mM LiCl, tissues areincubated for 30 min at room temperature with a buffer change at 15 min.Buffer is removed and Krebs-Henseleit buffer (containing 40 μg/mlbacitracin, 4 μg/ml each of leupeptin and chymostatin, 0.1% bovine serumalbumin and 10 μM of thiorphan and 10 mM of LiCl) including the testcompound is added. After 15 min, SP is added to UC11 cells or NKA toSKLKB82#3 cells at various concentrations to start the reaction. Afterincubation for 60 min at room temperature the reaction is terminated byaddition of 930 μl chloroform: methanol (1:2 by volume) to each tube,followed by 310 μl chloroform and 310 μl doubly distilled water. Samplesare vortexed, centrifuged, and 0.9 ml of the aqueous (top) phase removedand added to 2 ml doubly distilled H₂ O. The mixture is vortexed andloaded onto a 50% Bio-Rad AG 1-X8 (formate form, 100-200 mesh) exchangecolumn (Bio-Rad Laboratories, Hercules, Calif.). The columns are washed,in order, with: 1) 10 ml doubly distilled water, 2) 5 ml of 5 mMdisodium tetraborate/60 mM sodium formate, and 3) 5 ml of 1M ammoniumformate/0.1M formic acid. The third elution is collected and 1 mlcounted in 7 ml scintillation fluid. A 50 μl aliquot of the organic(bottom) phase is removed, dried in a scintillation vial and counted in7 ml scintillation fluid.

The ratio of DPM in the aqueous phase aliquot (total inositolphosphates) to the DPM in the 50 μl organic phase aliquot (total ³H!inositol incorporated) is calculated for each sample. Data areexpressed as a percent of agonist-induced accumulation of ³ H!-inositolphosphates over basal levels. The ratios in the presence of testcompound and/or standards are compared to the ratios for control samples(i.e. no stimulating agonist). Dose-response graphs are constructed andthe ability of the test compounds to inhibit tachykinin-inducedphosphatidyinositol turnover determined with the aid of a computerprogram. Data is expressed as percent stimulation of total inositolphosphate accumulation over basal levels and normalized to the maximumresponse produced by SP. Schild analysis is performed using doseresponse curves to obtain a value indicative of the strength of acompetitive antagonist and is expressed as the pA₂, which is thenegative logarithm of the molar concentration of antagonist whichreduces the effect of a dose of agonist to one-half of that expected atthe dose of agonist.

One skilled in the art can determine that the compounds of the presentintention are NK₁ receptor antagonists in vivo by evaluating thecompounds ability to inhibit SP-induced plasma protein extravasation inguinea pig trachea. SP-induced protein leakage through postcapillaryvenules is assessed by measuring Evans Blue dye accumulation in guineapig trachea. Animals are anesthetized with pentobarbital then injectedwith Evans Blue dye (20 mg/kg, i.v., prepared in 0.9% NaCl solution).One minute after dye administration, the antagonist is administered(i.v.) followed by SP (0.3 nmole/kg, i.v.) and, after 5 min, excess dyeremoved from the circulation by transcardiac perfusion with 50 ml 0.9%NaCl solution. The trachea and primary bronchi are removed, blotted dryand weighed. Dye quantitation is performed spectrophotometrically (620nM) after extracting tissues in formamide for 24 hr at 50° C. Values aresubtracted from background (dye only, no agonist). ED₅₀ (dose ofcompound which inhibits SP-induced plasma protein extravasation by 50%)is calculated from linear regression analysis.

One skilled in the art can determine that the compounds of the presentintention are NK₂ receptor antagonists in vivo by evaluating thecompounds ability to inhibit NKA-induced respiratory effects. Inaddition, both NK₁ and NK₂ antagonism can be evaluated afteradministration of capsaicin, which is known to release both SP and NKAfrom airway sensory nerves. Antagonism of NKA and capsaicin inducedrespiratory effects in conscious guinea pigs is carried out as follows.In vivo experiments are performed using male Duncan Hartley guinea pigs(250-350 g). Changes in conscious breathing patterns are monitored infour animals simultaneously using modified whole body plethysmographyconsisting of four small plexiglass boxes each connected to a referencebox via Validyne DP 45-16 differential pressure transducers. The 4 boxesare equipped with an air supply line (also used for aerosol delivery)and an exhaust air line. Supply and exhaust lines are of the same lengthand narrow bore and arise from a common supply chamber and vented to acommon exhaust chamber. This system is used to ensure that fluctuationsin supply air and atmospheric pressure remain in phase and be eliminatedfrom the net signal by the differential pressure transducers. The analogpressure signals are digitalized via a Data Translation DT2821 A to Dboard. Data are collected at a rate of 100 samples/second/animal. Eachcycle of pressure change is analyzed using the following parameters:rising and falling slope determined between minimum and maximumpressures, the ratio of rising over falling slope, and the magnitude ofthe change between initial trough pressure and peak cycle pressure.Using these values (and observing the animals) the pressure cycles arecharacterized into normal breaths, forced exhalations (apparent byabdominal heaving), significant respiratory events (SREs; usuallycoughs, less often sneezes or gasps which are characterized bytransient, extremely large pressure increases which are distinguishablefrom noise) and movement/noise with a PCAT 286 running a System V UNIXoperating system. Dyspnea is defined as a significant, sustainedincrease in plethysmograph pressure which is associated with anobservable shift to labored breathing in the animal.

During the course of a typical experiment in which airway responsivenessto various bronchoconstricting agents is examined, aerosols aredelivered for 19 min (0.33 ml/min) using a DeVilbiss Ultraneb 99ultrasonic nebulizer and animals monitored during this time. Prior tonebulization, 1 min of resting breathing is collected to establish abaseline pressure. In preliminary experiments, various concentrations ofthe bronchoconstrictive agents are evaluated and the concentrationchosen which maximized the number of animals exhibiting dyspnea butminimized the severity of the response. Hence, neurokinin A is deliveredat a final concentration of 0.05%, and capsaicin, 0.001%. The vehiclefor nebulization of all bronchoconstrictive agents is phosphate bufferedsaline (pH 7.4) which elicited no respiratory effects itself. Putativetachykinin antagonists are administered (i.v.) 20 min prior to onset ofaerosol exposure.

What is claimed is:
 1. A compound of the formula ##STR31## wherein Ar₁is a radical chosen from the group: ##STR32## wherein Z₁ is from 1 to 3substituents each independently chosen from the group consisting ofhydrogen, halogen, benzyloxy, hydroxy, CF₃, C₁ -C₄ alkyl, and C₁ -C₄alkoxy;R₂ is hydrogen, C₁ -C₄ alkyl, or --CHO; R₃ is hydrogen or aradical chosen from the group ##STR33## wherein Z₃ is from 1 to 3substituents each independently chosen from the group consisting ofhydrogen, halogen, benzyloxy, hydroxy, CF₃, C₁ -C₄ alkyl, and C₁ -C₄alkoxy; R₅ is hydrogen, benzyl, or C₁ -C₄ alkyl; R₆ is hydrogen or--C(O)OR₇ wherein R₇ is benzyl or C₁ -C₄ alkyl;or stereoisomers, orpharmaceutically acceptable salt thereof.
 2. A compound of claim 1wherein R₆ is --C(O)OR₇.
 3. A compound of claim 1 wherein R₆ ishydrogen.
 4. A compound of claim 1 wherein R₅ is methyl.
 5. A compoundof claim 1 wherein the compound is 2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2-phenyl-ethyl)-ethylamine.6. A compound of claim 1 wherein the compound is 2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2-phenyl-ethyl)-ethylamine.7. A compound of claim 1 wherein the compound is 2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2-phenyl-ethyl)-ethylamine.8. A compound of claim 1 wherein the compound is 2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2-phenyl-ethyl)-ethylamine.9. A compound of claim 1 wherein the compound is 2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-2- (4-benzyloxy)phenyl-ethyl!!-ethylamine.
 10. A compound of claim 1wherein the compound is 2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- 2-(4-benzyloxy)phenyl-ethyl!!-ethylamine.
 11. A compound of claim 1wherein the compound is 2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-2- (4-benzyloxy)phenyl-ethyl!!-ethylamine.
 12. A compound of claim 1wherein the compound is 2-(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N- 2-(4-benzyloxy)phenyl-ethyl!!-ethylamine.
 13. A compound of claim 1wherein the compound is 2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(t-butoxycarbonyl)-N-(2,2-bis-phenyl-ethyl)!-ethylamine.14. A compound of claim 2 wherein the compound is 2-(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino!-N-(2,2-bis-phenyl-ethyl)!-ethylamine.